1. Field of the Invention
This invention relates generally to processing of certain body tissues used in therapy, diagnosis and research. Such tissues include blood substances used in transfusions, as well certain organs and organ parts used in transplants. Thus the invention relates generally to blood substances, and to optical corneas and sclerae.
The invention relates more particularly to disinfecting such tissues--i. e., to disinfecting certain blood constituents, and corneas and sclerae. My invention may possibly also have future application to other transplant tissues.
For the purposes of this document, including the appended claims, I hereby define the phrase "blood constituent" to mean red blood cells, or blood platelets, or blood plasma. I also define the phrase "cellular blood constituent" to mean red blood cells, or blood platelets, but not plasma, or plasma proteins.
I further hereby define the phrase "blood product" to mean one or more blood constituents either alone or in combination, and either with or without other blood constituents or other substances. Thus one example of a "blood product" is whole blood, and another example is blood plasma.
This processing is designed to inactivate or greatly reduce the infectivity of certain harmful substances or contaminants, thus rendering the blood constituents, organs, or other tissues safe for human beneficial use--whether therapeutic, diagnostic, or experimental. Such harmful substances include, but are not limited to, several blood-borne viruses and other microorganisms as discussed below.
2. PRIOR ART
Human and animal tissues, particularly human blood products and corneal and scleral tissue (which encompasses parts of corneas and sclerae, as well as whole corneas and sclerae), are supplied for transfusion and transplantation purposes very commonly. There has been no way, however, to guarantee the safety of such tissues for transfusion or transplantation.
Transfusion of human blood products--particularly the constituents mentioned above--carries a well-known risk of transmitting harmful substances. The same is true of cornea, sclera, and other organ or organ-component transplants.
For the purposes of this document, including the appended claims, I hereby define the phrase "harmful substance" to mean a virus or other agent that can cause a disease or other harm.
Of particular interest are viruses that appear to cause various forms of hepatitis, including the hepatitis B virus; the non-A, non-B hepatitis virus or viruses. Others of interest are cytomegalovirus and Epstein-Barr virus.
Also of great interest is the virus, or group of viruses, linked with the incurable and often fatal disease known as acquired immune deficiency syndrome or "AIDS."0 This is probably caused by a retrovirus or group of retroviruses previously denominated "HTLV-III" and other HTLV types--and more currently "HIV", "HIV-1," "HIV-2," "HIV-3" and "HIV-4." The most common cause of AIDS is thought to be HTLV-III, now usually called HIV-1.
Detection and isolation of such cytopathic retroviruses from patients with AIDS, and certain members of groups that are at high risk for AIDS, have been frequently reported. One such report appears in Science 224:500-03 (1984).
Such findings are corroborated by P. S. Savin et al. in an article entitled "Human T-Lymphotrophic Retroviruses in Adult T-cell Leukemia-Lymphoma and Acquired Immune Deficiency Syndrome," J. Clinical Immunol. 4:415-23 (1984). Yet another report is by F. Wong-Staal and R. C. Gallo, "Human T-Lymphotrophic Retroviruses," Nature 317:395-402 (1985).
While the hazard of hepatitis and AIDS transmission through transfusion of blood products has received great public attention, the analogous hazard of such transmission through transplantation of eye tissues is a much less familiar matter. Nevertheless there is a recognized possibility of at least AIDS virus transmission from corneal transplantation, according to CORNEAL SURGERY Theory, Technique and Tissue, F. S. Brightbill, ed., p. 53 (Mosby 1986).
Furthermore, contamination of corneas by bacteria and fungi is documented, id. at 52, even though antibacterial solutions are commonly used in pretransplant storage of corneas--generally within the nutrient medium that supports the corneas. Hence this field of surgery also has need for a more effective means of controlling bacterial and fungal invasion.
For purposes of biomedical research, analysis and therapy it is of course very important to understand and use all of the distinctions between different kinds of virus or viruses that cause or at least are linked with various forms of hepatitis and AIDS. For present purposes of this document, however, it would be cumbersome and unnecessary to carry this multiplicity of distinctions and alternatives throughout my discussion.
Accordingly, in the interest of conciseness, throughout the following parts of this document I shall use a more general terminology. I shall refer to the various hepatitis viruses in a more general way as simply "hepatitis virus," and to the HTLV or HIV series, or both, simply as "AIDS virus."
In doing so I do not mean to detract in the slightest from the importance of the distinctions and uncertainties associated with the various nomenclatures. Thus a hepatitis virus is a "harmful substance," as is an AIDS virus, and of course there are other such substances.
There is an important need to make human blood products, human corneas and sclerae, and other tissues used as transfusions and transplants safe from all such harmful substances. Until now, this critically urgent need has gone unmet.
I shall now discuss two different developments of roughly the last ten years which are relevant to my invention--but which heretofore have been unrelated to the problem of viral contamination of transfusions and transplants. The first of these is the development of new disinfectants that are capable of inactivating these viruses.
In particular, Sarin et al. have reported that a particular commercially available laboratory disinfectant can completely inactivate at least one form of AIDS virus. Sarin et al., however, make no mention or suggestion of applying the disinfectant to blood products or tissue transplants.
The disinfectant is composed of approximately 0.23 percent sodium chlorite and 1.26 percent lactic acid, and is marketed under the name LD.RTM. by Alcide Corporation of Norwalk, Conn. The manufacturer directs that LD be diluted in distilled water before use. Sarin et al. reportedly used it at dilutions of 1:200 and 1:100 or less, in water, as they describe in New Engl. J. Med. 33:1416 (1985).
The subject disinfectant corresponds to a composition which is patented by Howard Alliger in U.S. Pat. No. Re. 31,779. According to his patent, he prefers sodium chlorite as a chlorine-dioxide-liberating material; but he suggests substitution of "other water-solubilizing cations"--e. g., other alkali metals such as potassium, and alkaline-earth metals.
Alliger also indicates that up to eighty-five percent of the lactic acid may be replaced by other acids, preferably with analogous structure. Organic acids expressly enumerated include acetic, citric, sorbic, fumaric and tannic; and inorganic acids mentioned include sulfuric, hydrochloric and phosphoric.
Alliger, as with Sarin et al., makes no mention or suggestion of applying the disinfectant to blood products for transfusion, or to corneal, scleral, or other tissues intended for transplant. To the contrary, he asserts that certain components--particularly the lactic acid--of the subject disinfectant impart to it an extraordinary natural affinity for the material of cell walls, and thus accessibility to the interiors of cells.
This property assertedly or apparently results in effective invasion of bacterial cells, with consequent bactericidal action--sometimes perhaps including lysis. If a suggestion were made to use such a disinfectant for the external portions of blood products or transplant tissues, then based upon Alliger's disclosure such a suggestion would probably be rejected--since one might expect the disinfectant to invade and injure blood cells, platelets, or transplant tissues too.
My invention relates to three types of tissues: cellular blood constituents, noncellular blood constituents or plasma, and eye components. At this point in the discussion it will be helpful to briefly discuss these three separately to clarify certain contrasts among them.
With respect to cellular blood constituents in particular, as far as I know, heretofore no disinfectant has been used or suggested. If such a suggestion were made, it would generally be discounted for two reasons.
First, in general disinfectants strong enough to significantly inactivate viruses would damage the cellular constituents. Secondly, with such a strong chemical, any residual disinfectant in the cellular constituents to be transfused could be hazardous to the recipient of the transfusion.
With respect to corneal and scleral tissue, as noted above, the most potent prophylactic substances now used are antibacterials, and even these apparently are of questionable efficacy. Hence it may be understood that in this delicate context even antibacterials must be relatively mild in their effects to be useful at all.
With respect to blood-plasma treatment, the situation is somewhat more complicated. Whereas in the case of cellular blood products no disinfectants have heretofore been known, and in the case of corneas only mild antibacterials have heretofore been known, in the case of plasma disinfection at least one potent disinfectant has been placed in commercial use.
That material is beta-propiolactone. In this field it is usually employed to disinfect plasma preliminary to fractionation. Such a process has been used for isolation of therapeutic immune globulin, Factor VIII and IX, and other proteins.
Beta-propiolactone, however, is a known carcinogen and hence potentially very dangerous. To the extent that significant residual quantities of this material may remain in the blood product which is actually transfused, the use of propiolactone may possibly represent a significant hazard.
The other relatively recent development which is relevant to my invention--but not previously connected effectively with disinfection of blood constituents--is the introduction of automated cell washers (e.g., the IBM Model 2292 Cell Washer). These devices can wash red blood cells or platelets, or coagulated plasma proteins.
Automated cell washers are programmable to put very large quantities of biological cells through a predetermined cycle of chemical exposures, rinses, spins, and so forth. The machines accomplish this with great precision and reliability on a high-volume production-line basis.
At the same time, however, they can be made to apply such procedural steps to cells while the cells are kept in individual relatively small discrete volumes--such as, in particular, the "units" in which blood donations are received--thereby avoiding various problems inherent in pooling of donations. Heretofore, however, cell washers have not played any role in ameliorating the problems of viral contamination discussed above.
Thus no process to eliminate or lessen transmission of harmful substances in transfusion of blood constituents, or in transplantation of organs or organ parts such as corneal and scleral tissue, has been available.